elNoire
i prefer sleeping
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human growth is not one simple process it's the coordination of systemic hormones (like GH and IGF-1) with intracellular molecular pathways (like PI3K–AKT–mTOR) to cause:
Increasing bonemass
longitudinal bone growth (height)
hypertrophy
organ development
protein synthesis and cell division
the master hormone here is Growth Hormone (GH), but it acts indirectly via Insulin-like Growth Factor 1 (IGF-1), which then activates intracellular growth machinery: PI3K → AKT → mTOR.
GH initiates the growth signal
GH is secreted in pulses by the anterior pituitary, especially at night during deep sleep and after exercise/fasting. GH enters the bloodstream and reaches all tissues, especially the liver, bones, and muscles.
GH receptor binding
GH binds to GH receptors (GHRs) on the surface of liver cells, chondrocytes (cartilage cells), and muscle cells. This activates JAK2–STAT5 signaling, which does two key things:
1. In Liver: Produces IGF-1.
GH induces transcription of IGF-1 gene in liver.
IGF-1 is secreted into the bloodstream.
2. In Target Tissues: Primes them for IGF-1 action.
GH can also upregulate IGF-1 receptor expression in muscle and bone to prepare them to respond.
IGF-1: the growth executioner
IGF-1 Travels via Blood. IGF-1 travels from the liver to growth plates, muscles, and other tissues. It also acts locally (autocrine/paracrine) where it's produced — e.g., by bones or muscles themselves in response to GH or mechanical stress.
IGF-1 Receptor Activation
IGF-1 binds to the IGF-1 receptor, a receptor tyrosine kinase on the plasma membrane. This activates the intracellular PI3K–AKT–mTOR cascade. PI3K, AKT, mTOR: the intercellular growth program
Now that IGF-1 is bound to its receptor, the growth program inside the cell begins.
- PI3K Activation
IGF-1R phosphorylates IRS-1, which recruits PI3K. PI3K converts PIP2 → PIP3 in the cell membrane.
AKT recruitment & activation
AKT also called Protein Kinase B is attracted to PIP3 via its PH domain. it is phosphorylated at two key sites:
Thr308 by PDK1
Ser473 by mTORC2
Now AKT is fully active.
then AKT executes growth orders
AKT performs many growth-supporting actions:
- Inhibits apoptosis (cell death)
Phosphorylates and inactivates BAD, FOXO → cells stay alive and ready to grow.
- Promotes metabolism
Increases glucose uptake (GLUT4) and glycogen synthesis for energy needs.
- Activates mTORC1
Phosphorylates and inhibits TSC2, which normally represses Rheb. Active Rheb-GTP activates mTORC1, the true growth switch.
mTORC1 = PROTEIN SYNTHESIS AND GROWTH
now mTORC1 initiates the building phase:
A. Protein Synthesis
Phosphorylates S6K1 → stimulates ribosome production. Phosphorylates 4E-BP1 → frees up eIF4E → allows mRNA translation to begin.
result: thousands of proteins needed for cell structure, enzymes, hormones, etc., are synthesized.
B. Lipid and Nucleotide Synthesis
mTORC1 supports synthesis of membranes and nucleotides for growing/dividing cells.
C. Inhibits Autophagy
mTORC1 inhibits ULK1, suppressing cellular self-digestion so that building, not breaking down, dominates.
Growth at the tissue level.
Now let’s zoom out to see what this cascade causes in the actual body:
A. Bone Growth (Height):
At the epiphyseal growth plates, GH stimulates chondrocyte proliferation, and IGF-1 promotes:
Chondrocyte hypertrophy
Matrix production
Ossification
mTOR in these cells helps them grow in size and divide → longitudinal bone growth.
B. Muscle Growth (Hypertrophy)
GH promotes amino acid uptake and fat use for energy. IGF-1 stimulates satellite cells (muscle stem cells) to proliferate and fuse into existing fibers. Inside muscle cells, mTORC1 ramps up protein synthesis:
More actin, myosin, titin, and enzymes → muscle fibers grow thicker and stronger.
C. Organ Growth
Liver, kidneys, pancreas, and heart all express IGF-1R and respond by growing during development. mTOR ensures increased ribosome biogenesis and metabolic machinery to support organ size/function.
D. Metabolism Support
GH increases lipolysis → frees fatty acids for energy. IGF-1 + AKT increase glucose uptake and glycogen storage to fuel growth. mTOR integrates nutrient signals (like amino acids) with hormone signals to ensure resources are available.
Negative feedback & balance
Growth must be controlled to prevent cancer or gigantism.
A. IGF-1 Negative Feedback
High levels of IGF-1:
Inhibit GHRH secretion from the hypothalamus
Increase somatostatin, which inhibits GH release
B. PTEN Turns Off AKT Pathway
PTEN dephosphorylates PIP3 → PIP2, stopping AKT activation.
C. AMPK Inhibits mTOR in Low Energy States
When cellular energy is low (high AMP), AMPK blocks mTOR, halting growth until ATP is restored.
COMPLETE PATHWAY SUMMARY (IN ORDER)
1. Hypothalamus → GHRH
2. Pituitary → GH
3. GH → Liver → IGF-1
4. IGF-1 binds to IGF-1R → activates PI3K
5. PI3K → converts PIP2 to PIP3
6. PIP3 → recruits AKT
7. AKT activated → inhibits TSC2
8. Rheb activated → activates mTORC1
9. mTORC1 → stimulates protein synthesis, cell growth, and inhibits autophagy
10. Tissue-level effects:
- Bones grow longer
- Muscles grow thicker
- Organs enlarge
- Energy metabolism supports growth
GH starts the signal. IGF-1 amplifies and spreads the signal. PI3K–AKT–mTOR executes the growth program inside cells. Together, they grow your height, muscle, bones, organs, and metabolic support systems.
HOW GH, IGF-1, PI3K, AKT, AND mTOR INCREASE BONE MASS
What's bonemass?
“Bone mass” refers to the total amount of bone tissue in the skeleton, including:
Bone mineral density (BMD) – primarily calcium and phosphate
Bone volume and thickness
Trabecular (spongy) bone and cortical (compact) bone. Increasing bone mass = increasing osteoblast activity, mineral deposition, and bone matrix protein synthesis, while maintaining or reducing bone resorption (osteoclast activity).
Roles Of Gh And Igf-1 In Bone
A. GH: The Initiator
GH acts directly on bone-forming cells (osteoblasts) and indirectly by stimulating IGF-1.
GH increases:
Proliferation of osteoprogenitor cells
Local production of IGF-1 in the bone
Calcium retention in kidneys → more mineral for bone
B. IGF-1: The Local Growth Commander
IGF-1 is produced both:
Systemically (from liver)
Locally in bone (autocrine/paracrine)
IGF-1 promotes:
Osteoblast proliferation
Matrix protein synthesis (e.g., collagen type I)
Osteoblast survival
Mineralization of bone
Cellular Targets: Osteoblasts & Bone Marrow Stromal Cells
Bone formation is driven mainly by osteoblasts, derived from mesenchymal stem cells (MSCs).
GH and IGF-1 activate these MSCs to:
1. Proliferate
2. Differentiate into pre-osteoblasts and then mature osteoblasts
3. Lay down new bone matrix (osteoid)
4. Mineralize the matrix with calcium and phosphate
This is where the PI3K–AKT–mTOR pathway becomes essential.
How Pi3k–AKT–mTOR Signaling Drives Bone Mass Increase.
- IGF-1 BINDS TO IGF-1R ON OSTEOBLASTS
Activates the IGF-1 receptor (IGF-1R) on osteoblasts and progenitor cells.
Triggers PI3K recruitment via IRS-1.
- PI3K → AKT ACTIVATION
PI3K generates PIP3, recruiting AKT.
AKT gets fully activated (Thr308 + Ser473).
AKT promotes:
Cell survival: inhibits apoptosis of osteoblasts
Cell proliferation: expands the osteoblast pool
Runx2 activation: key transcription factor for osteoblast genes
mTORC1 ACTIVATION = BONE MATRIX PROTEIN SYNTHESIS
AKT inhibits TSC2 → activates Rheb → activates mTORC1
mTORC1 phosphorylates:
S6K1 → increases ribosome biogenesis
4E-BP1 → increases protein translation
This leads to massive synthesis of bone matrix proteins, especially:
Type I collagen (most abundant bone protein)
Osteocalcin
Alkaline phosphatase
Matrix Gla protein
Bone sialoprotein
All of these are essential for the osteoid (organic bone matrix) formation.
Matrix Mineralization
mTORC1 also supports energy and lipid metabolism in osteoblasts, helping them:
Transport calcium and phosphate
Produce ATP for mineral deposition
These steps result in hydroxyapatite crystals forming in the matrix.
GH vs IGF-1 on Bone
AspectGH & IGF-1
SourcePituitaryLiver (and local bone)
Action SiteIndirect and directDirect on bone cells
Main RoleStimulates IGF-1 + stem cellsDrives osteoblast growth
ReceptorGHRIGF-1R
Key PathwayJAK-STATPI3K–AKT–mTOR
Other Factors That Work With GH/IGF-1
Testosterone + Estrogen → synergize with IGF-1 for bone growth and closure of growth plates.
Mechanical Loading (e.g., exercise) → also activates mTOR in bone via integrins and mechanosensors.
Vitamin D, calcium, magnesium → required for mineralization, not directly linked to this pathway but essential downstream.
SUMMARY: GH/IGF-1–mTOR = BONE MASS BUILDER
1. GH triggers IGF-1 production.
2. IGF-1 activates PI3K–AKT–mTOR in osteoblasts.
3. AKT promotes survival, proliferation, and differentiation of bone-forming cells.
4. mTORC1 drives protein synthesis and mineralization of new bone.
5. Result: thicker, denser, and stronger bone
I've been saving it since idk. Correct me if I'm wrong, i dont think I'm all correct but just correct if something wrong sirr
. hope this helps y'all, dont judge/mock
Increasing bonemass
longitudinal bone growth (height)
hypertrophy
organ development
protein synthesis and cell division
the master hormone here is Growth Hormone (GH), but it acts indirectly via Insulin-like Growth Factor 1 (IGF-1), which then activates intracellular growth machinery: PI3K → AKT → mTOR.
GH initiates the growth signal
GH is secreted in pulses by the anterior pituitary, especially at night during deep sleep and after exercise/fasting. GH enters the bloodstream and reaches all tissues, especially the liver, bones, and muscles.
GH receptor binding
GH binds to GH receptors (GHRs) on the surface of liver cells, chondrocytes (cartilage cells), and muscle cells. This activates JAK2–STAT5 signaling, which does two key things:
1. In Liver: Produces IGF-1.
GH induces transcription of IGF-1 gene in liver.
IGF-1 is secreted into the bloodstream.
2. In Target Tissues: Primes them for IGF-1 action.
GH can also upregulate IGF-1 receptor expression in muscle and bone to prepare them to respond.
IGF-1: the growth executioner
IGF-1 Travels via Blood. IGF-1 travels from the liver to growth plates, muscles, and other tissues. It also acts locally (autocrine/paracrine) where it's produced — e.g., by bones or muscles themselves in response to GH or mechanical stress.
IGF-1 Receptor Activation
IGF-1 binds to the IGF-1 receptor, a receptor tyrosine kinase on the plasma membrane. This activates the intracellular PI3K–AKT–mTOR cascade. PI3K, AKT, mTOR: the intercellular growth program
Now that IGF-1 is bound to its receptor, the growth program inside the cell begins.
- PI3K Activation
IGF-1R phosphorylates IRS-1, which recruits PI3K. PI3K converts PIP2 → PIP3 in the cell membrane.
AKT recruitment & activation
AKT also called Protein Kinase B is attracted to PIP3 via its PH domain. it is phosphorylated at two key sites:
Thr308 by PDK1
Ser473 by mTORC2
Now AKT is fully active.
then AKT executes growth orders
AKT performs many growth-supporting actions:
- Inhibits apoptosis (cell death)
Phosphorylates and inactivates BAD, FOXO → cells stay alive and ready to grow.
- Promotes metabolism
Increases glucose uptake (GLUT4) and glycogen synthesis for energy needs.
- Activates mTORC1
Phosphorylates and inhibits TSC2, which normally represses Rheb. Active Rheb-GTP activates mTORC1, the true growth switch.
mTORC1 = PROTEIN SYNTHESIS AND GROWTH
now mTORC1 initiates the building phase:
A. Protein Synthesis
Phosphorylates S6K1 → stimulates ribosome production. Phosphorylates 4E-BP1 → frees up eIF4E → allows mRNA translation to begin.
result: thousands of proteins needed for cell structure, enzymes, hormones, etc., are synthesized.
B. Lipid and Nucleotide Synthesis
mTORC1 supports synthesis of membranes and nucleotides for growing/dividing cells.
C. Inhibits Autophagy
mTORC1 inhibits ULK1, suppressing cellular self-digestion so that building, not breaking down, dominates.
Growth at the tissue level.
Now let’s zoom out to see what this cascade causes in the actual body:
A. Bone Growth (Height):
At the epiphyseal growth plates, GH stimulates chondrocyte proliferation, and IGF-1 promotes:
Chondrocyte hypertrophy
Matrix production
Ossification
mTOR in these cells helps them grow in size and divide → longitudinal bone growth.
B. Muscle Growth (Hypertrophy)
GH promotes amino acid uptake and fat use for energy. IGF-1 stimulates satellite cells (muscle stem cells) to proliferate and fuse into existing fibers. Inside muscle cells, mTORC1 ramps up protein synthesis:
More actin, myosin, titin, and enzymes → muscle fibers grow thicker and stronger.
C. Organ Growth
Liver, kidneys, pancreas, and heart all express IGF-1R and respond by growing during development. mTOR ensures increased ribosome biogenesis and metabolic machinery to support organ size/function.
D. Metabolism Support
GH increases lipolysis → frees fatty acids for energy. IGF-1 + AKT increase glucose uptake and glycogen storage to fuel growth. mTOR integrates nutrient signals (like amino acids) with hormone signals to ensure resources are available.
Negative feedback & balance
Growth must be controlled to prevent cancer or gigantism.
A. IGF-1 Negative Feedback
High levels of IGF-1:
Inhibit GHRH secretion from the hypothalamus
Increase somatostatin, which inhibits GH release
B. PTEN Turns Off AKT Pathway
PTEN dephosphorylates PIP3 → PIP2, stopping AKT activation.
C. AMPK Inhibits mTOR in Low Energy States
When cellular energy is low (high AMP), AMPK blocks mTOR, halting growth until ATP is restored.
COMPLETE PATHWAY SUMMARY (IN ORDER)
1. Hypothalamus → GHRH
2. Pituitary → GH
3. GH → Liver → IGF-1
4. IGF-1 binds to IGF-1R → activates PI3K
5. PI3K → converts PIP2 to PIP3
6. PIP3 → recruits AKT
7. AKT activated → inhibits TSC2
8. Rheb activated → activates mTORC1
9. mTORC1 → stimulates protein synthesis, cell growth, and inhibits autophagy
10. Tissue-level effects:
- Bones grow longer
- Muscles grow thicker
- Organs enlarge
- Energy metabolism supports growth
GH starts the signal. IGF-1 amplifies and spreads the signal. PI3K–AKT–mTOR executes the growth program inside cells. Together, they grow your height, muscle, bones, organs, and metabolic support systems.
HOW GH, IGF-1, PI3K, AKT, AND mTOR INCREASE BONE MASS
What's bonemass?
“Bone mass” refers to the total amount of bone tissue in the skeleton, including:
Bone mineral density (BMD) – primarily calcium and phosphate
Bone volume and thickness
Trabecular (spongy) bone and cortical (compact) bone. Increasing bone mass = increasing osteoblast activity, mineral deposition, and bone matrix protein synthesis, while maintaining or reducing bone resorption (osteoclast activity).
Roles Of Gh And Igf-1 In Bone
A. GH: The Initiator
GH acts directly on bone-forming cells (osteoblasts) and indirectly by stimulating IGF-1.
GH increases:
Proliferation of osteoprogenitor cells
Local production of IGF-1 in the bone
Calcium retention in kidneys → more mineral for bone
B. IGF-1: The Local Growth Commander
IGF-1 is produced both:
Systemically (from liver)
Locally in bone (autocrine/paracrine)
IGF-1 promotes:
Osteoblast proliferation
Matrix protein synthesis (e.g., collagen type I)
Osteoblast survival
Mineralization of bone
Cellular Targets: Osteoblasts & Bone Marrow Stromal Cells
Bone formation is driven mainly by osteoblasts, derived from mesenchymal stem cells (MSCs).
GH and IGF-1 activate these MSCs to:
1. Proliferate
2. Differentiate into pre-osteoblasts and then mature osteoblasts
3. Lay down new bone matrix (osteoid)
4. Mineralize the matrix with calcium and phosphate
This is where the PI3K–AKT–mTOR pathway becomes essential.
How Pi3k–AKT–mTOR Signaling Drives Bone Mass Increase.
- IGF-1 BINDS TO IGF-1R ON OSTEOBLASTS
Activates the IGF-1 receptor (IGF-1R) on osteoblasts and progenitor cells.
Triggers PI3K recruitment via IRS-1.
- PI3K → AKT ACTIVATION
PI3K generates PIP3, recruiting AKT.
AKT gets fully activated (Thr308 + Ser473).
AKT promotes:
Cell survival: inhibits apoptosis of osteoblasts
Cell proliferation: expands the osteoblast pool
Runx2 activation: key transcription factor for osteoblast genes
mTORC1 ACTIVATION = BONE MATRIX PROTEIN SYNTHESIS
AKT inhibits TSC2 → activates Rheb → activates mTORC1
mTORC1 phosphorylates:
S6K1 → increases ribosome biogenesis
4E-BP1 → increases protein translation
This leads to massive synthesis of bone matrix proteins, especially:
Type I collagen (most abundant bone protein)
Osteocalcin
Alkaline phosphatase
Matrix Gla protein
Bone sialoprotein
All of these are essential for the osteoid (organic bone matrix) formation.
Matrix Mineralization
mTORC1 also supports energy and lipid metabolism in osteoblasts, helping them:
Transport calcium and phosphate
Produce ATP for mineral deposition
These steps result in hydroxyapatite crystals forming in the matrix.
GH vs IGF-1 on Bone
AspectGH & IGF-1
SourcePituitaryLiver (and local bone)
Action SiteIndirect and directDirect on bone cells
Main RoleStimulates IGF-1 + stem cellsDrives osteoblast growth
ReceptorGHRIGF-1R
Key PathwayJAK-STATPI3K–AKT–mTOR
Other Factors That Work With GH/IGF-1
Testosterone + Estrogen → synergize with IGF-1 for bone growth and closure of growth plates.
Mechanical Loading (e.g., exercise) → also activates mTOR in bone via integrins and mechanosensors.
Vitamin D, calcium, magnesium → required for mineralization, not directly linked to this pathway but essential downstream.
SUMMARY: GH/IGF-1–mTOR = BONE MASS BUILDER
1. GH triggers IGF-1 production.
2. IGF-1 activates PI3K–AKT–mTOR in osteoblasts.
3. AKT promotes survival, proliferation, and differentiation of bone-forming cells.
4. mTORC1 drives protein synthesis and mineralization of new bone.
5. Result: thicker, denser, and stronger bone
I've been saving it since idk. Correct me if I'm wrong, i dont think I'm all correct but just correct if something wrong sirr
. hope this helps y'all, dont judge/mock
